Selectivity in the Interrupted Nazarov Reaction

Abstract

Three allenyl vinyl ketones (AVKs) underwent Lewis acid-mediated Nazarov cyclization in the presence of a variety of dienes. Products arising from the (4+3)- and (3+2)-cycloaddition to the oxyallyl cation intermediate of the Nazarov reaction were obtained. In general, (4+3) products were preferred but heavy substitution of a terminus of the diene led to (3+2) products. Some of the (3+2) products rearranged upon exposure to BF3•OEt2, but decomposition was a major competing process. The Gibbs energies of the Nazarov and rearranged products were compared computationally. AVKs with terminally substituted allenes were synthesized. The AVKs underwent Nazarov cyclization promoted by BF3•OEt2 and the oxyallyl cation was trapped by a (4+3)-cycloaddition. The products arose preferentially from cyclization where the terminal allenic substituent had rotated away from the vinyl group. The experimental results suggested that this selectivity was due to steric interactions between allenic and vinyl substituents. If any substituent on the AVK was larger than a methyl group, the torquoselectivity of the process was high. The torquoselectivity was not significantly affected by trapping via (4+3)- or (3+2)-cycloaddition. The products were stable to the reaction conditions. Calculations confirmed the kinetic preference for the observed products and supported the steric rationale for the torquoselectivity. The degree of deformation of the allene in the transition state was identified as a second factor in determining torquoselectivity. A synthetic method to access AVKs bearing tethered 1,3-dienes, with variable substitution and length, was developed. The dienes were installed using a Julia-Kocienski coupling reaction with an α,β-unsaturated aldehyde to give predominately the E-alkenes. Organometallic coupling was carried out using a Grignard reaction to form homopropargyl alcohols. The alcohols were oxidized using Dess-Martin periodinane or 2-iodoxybenzoic acid, and isomerized to AVKs with K2CO3. When exposed to BF3•OEt2 these molecules underwent a tandem Nazarov/(4+3) or (3+2)-cycloaddition. With a three-carbon tether the cycloaddition was (4+3), while with a four-carbon tether the cycloaddition was (3+2). Diene substitution had a significant effect on the stereoselectivity. In some cases very high diastereoselectivity was observed.